FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4206712553> ?p ?o ?g. }

• W4206712553 abstract "Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. New generation of VCP inhibitors needs to be evaluated in a mouse model of VCP disease. In this study, we tested the safety and efficacy of a novel and potent VCP inhibitor, CB-5083 using VCP patient-derived myoblast cells and an animal model of VCP disease.First, we analyzed the effect of CB-5083 in patient-derived myoblasts on the typical disease autophagy and TDP-43 profile by Western blot. Next, we determined the maximum tolerated dosage of CB-5083 in mice and treated the 2-month-old VCPR155H/R155H mice for 5 months with 15 mg/kg CB-5083. We analyzed motor function monthly by Rotarod; and we assessed the end-point blood toxicology, and the muscle and brain pathology, including autophagy and TDP-43 profile, using Western blot and immunohistochemistry. We also treated 12-month-old VCPR155H/+ mice for 6 months and performed similar analysis. Finally, we assessed the potential side effects of CB-5083 on retinal function, using electroretinography in chronically treated VCPR155H/155H mice.In vitro analyses using patient-derived myoblasts confirmed that CB-5083 can modulate expression of the proteins in the autophagy pathways. We found that chronic CB-5083 treatment is well tolerated in the homozygous mice harboring patient-specific VCP variant, R155H, and can ameliorate the muscle pathology characteristic of the disease. VCP-associated pathology biomarkers, such as elevated TDP-43 and p62 levels, were significantly reduced. Finally, to address the potential adverse effect of CB-5083 on visual function observed in a previous oncology clinical trial, we analyzed retinal function in mice treated with moderate doses of CB-5083 for 5 months and documented the absence of permanent ocular toxicity.Altogether, these findings suggest that long-term use of CB-5083 by moderate doses is safe and can improve VCP disease-associated muscle pathology. Our results provide translationally relevant evidence that VCP inhibitors could be beneficial in the treatment of VCP disease." @default.
• W4206712553 created "2022-01-25" @default.
• W4206712553 creator A5000020804 @default.
• W4206712553 creator A5015397813 @default.
• W4206712553 creator A5019245142 @default.
• W4206712553 creator A5020088480 @default.
• W4206712553 creator A5035223889 @default.
• W4206712553 creator A5035880873 @default.
• W4206712553 creator A5039756712 @default.
• W4206712553 creator A5042406450 @default.
• W4206712553 creator A5043030783 @default.
• W4206712553 creator A5045657649 @default.
• W4206712553 creator A5052610223 @default.
• W4206712553 creator A5054611483 @default.
• W4206712553 creator A5066054278 @default.
• W4206712553 creator A5073578477 @default.
• W4206712553 date "2022-01-08" @default.
• W4206712553 modified "2023-10-14" @default.
• W4206712553 title "VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy" @default.
• W4206712553 cites W1611974981 @default.
• W4206712553 cites W1885748186 @default.
• W4206712553 cites W1966067304 @default.
• W4206712553 cites W1967559627 @default.
• W4206712553 cites W1968731846 @default.
• W4206712553 cites W1974256456 @default.
• W4206712553 cites W1989634299 @default.
• W4206712553 cites W1999275385 @default.
• W4206712553 cites W2011754116 @default.
• W4206712553 cites W2018325704 @default.
• W4206712553 cites W2035974356 @default.
• W4206712553 cites W2051490456 @default.
• W4206712553 cites W2056607803 @default.
• W4206712553 cites W2079939478 @default.
• W4206712553 cites W2087654862 @default.
• W4206712553 cites W2089587945 @default.
• W4206712553 cites W2097097435 @default.
• W4206712553 cites W2099208822 @default.
• W4206712553 cites W2116170771 @default.
• W4206712553 cites W2116295762 @default.
• W4206712553 cites W2117279697 @default.
• W4206712553 cites W2126753299 @default.
• W4206712553 cites W2127803607 @default.
• W4206712553 cites W2140131487 @default.
• W4206712553 cites W2153811192 @default.
• W4206712553 cites W2156240486 @default.
• W4206712553 cites W2156739666 @default.
• W4206712553 cites W2262506123 @default.
• W4206712553 cites W2303275197 @default.
• W4206712553 cites W2311476251 @default.
• W4206712553 cites W2587856621 @default.
• W4206712553 cites W2602529236 @default.
• W4206712553 cites W2615692656 @default.
• W4206712553 cites W2736051823 @default.
• W4206712553 cites W2753357806 @default.
• W4206712553 cites W2769912066 @default.
• W4206712553 cites W2899020985 @default.
• W4206712553 cites W2900156386 @default.
• W4206712553 cites W2909114764 @default.
• W4206712553 cites W2910987379 @default.
• W4206712553 cites W2979586066 @default.
• W4206712553 cites W3034011428 @default.
• W4206712553 cites W3126098507 @default.
• W4206712553 cites W3158627946 @default.
• W4206712553 doi "https://doi.org/10.1186/s12967-021-03186-6" @default.
• W4206712553 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34998409" @default.
• W4206712553 hasPublicationYear "2022" @default.
• W4206712553 type Work @default.
• W4206712553 citedByCount "6" @default.
• W4206712553 countsByYear W42067125532022 @default.
• W4206712553 countsByYear W42067125532023 @default.
• W4206712553 crossrefType "journal-article" @default.
• W4206712553 hasAuthorship W4206712553A5000020804 @default.
• W4206712553 hasAuthorship W4206712553A5015397813 @default.
• W4206712553 hasAuthorship W4206712553A5019245142 @default.
• W4206712553 hasAuthorship W4206712553A5020088480 @default.
• W4206712553 hasAuthorship W4206712553A5035223889 @default.
• W4206712553 hasAuthorship W4206712553A5035880873 @default.
• W4206712553 hasAuthorship W4206712553A5039756712 @default.
• W4206712553 hasAuthorship W4206712553A5042406450 @default.
• W4206712553 hasAuthorship W4206712553A5043030783 @default.
• W4206712553 hasAuthorship W4206712553A5045657649 @default.
• W4206712553 hasAuthorship W4206712553A5052610223 @default.
• W4206712553 hasAuthorship W4206712553A5054611483 @default.
• W4206712553 hasAuthorship W4206712553A5066054278 @default.
• W4206712553 hasAuthorship W4206712553A5073578477 @default.
• W4206712553 hasBestOaLocation W42067125531 @default.
• W4206712553 hasConcept C104317684 @default.
• W4206712553 hasConcept C126322002 @default.
• W4206712553 hasConcept C142724271 @default.
• W4206712553 hasConcept C190283241 @default.
• W4206712553 hasConcept C203522944 @default.
• W4206712553 hasConcept C204232928 @default.
• W4206712553 hasConcept C207200792 @default.
• W4206712553 hasConcept C2776415932 @default.
• W4206712553 hasConcept C2777300911 @default.
• W4206712553 hasConcept C55493867 @default.
• W4206712553 hasConcept C71924100 @default.
• W4206712553 hasConcept C86803240 @default.
• W4206712553 hasConceptScore W4206712553C104317684 @default.
• W4206712553 hasConceptScore W4206712553C126322002 @default.

• next